The present invention relates to hexa- and octahydrobenzo[f]quinolinones, pharmaceutical formulations containing those compounds and their use as steroid 5.alpha.-reductase inhibitors.
It is generally known that certain undesirable physiological conditions such as benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutism and prostatic cancer are androgen mediated conditions dependent on 5.alpha.-dihydrotestosterone (DHT).
The enzyme 5.alpha.-reductase mediates the conversion of testosterone to the more potent androgen DHT locally, in the target organ. It has been postulated, and demonstrated, that inhibitors of 5.alpha.-reductase should block the formation of DHT and bring about amelioration of the above undesirable physiological conditions. Recently, two 5.alpha.-reductase isozymes (designated types 1 and 2) have been described in humans, Andersson et al., Proc. Natl. Acad. Sci. U.S.A., 87, 3640-3644 (1990; Andersson et al., Nature, 354, 159-161 (1991). In addition to certain structural differences, the two isozymes exhibit some differences with respect to their biochemical properties, expression patterns, genetics, and pharmacology, Andersson et al., Nature, 354, 159-161 (1991); Jenkins, et al., Journal of Clinical Investigation, 89, 293-300 (1992). Further elucidation of the roles that the two 5.alpha.-reductase isozymes play in androgen action is currently the subject of intense research. These isozymes are generally described as 5.alpha.-reductase 1 or 2, or type 1 or type 2 5.alpha.-reductase.
Compounds reportedly useful for inhibiting reductase are generally steroid derivatives such as the azasteroids in Rasmusson, et al., J. Med. Chem., 29, (11), 2298-2315 (1986); and benzoylaminophenoxy-butanoic acid derivatives such as those disclosed in EPO 291 245.
Certain benzo[f]quinolinone compounds are known. See for example Cannon, et al., Synthesis, 6, 494-496 (1986); Kiguchi, et al., Heterocycles, 18, (Special issue), 217-220 (1982); Cannon et al., J. Med. Chem., 22 (4), 341-347 (1979); Cannon, et al., J. Med. Chem., 23 (1), 1-5 (1980); Ninomiya, et al., J. Med. Chem. Soc. Perkin Trans. 1, 12, 2911-2917 (1984; and Horri, et al., Chem. Pharm. Bull., 16, (4), 668-671 (1968). These references generally are directed toward the synthesis and dopaminergic evaluation of the compounds disclosed therein. The references do not suggest the novel hexa- and octahydrobenzo[f]quinolinones of the present invention, as defined below, or that such compounds would be expected to have utility as steroid 5.alpha.-reductase inhibitors.
Accordingly, it is one object of the present invention to provide novel hexa- and octahydrobenzo[f]quinolinones which are potent selective steroid-5.alpha.-reductase inhibitors useful in the treatment of benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutism and prostatic cancer.
A further object of the present invention is to provide therapeutic compositions for treating said conditions.
Still another object is to provide methods for treating said conditions.
Other objects, features and advantages will become apparent to those skilled in the art from the following description and claims.